Made available in DSpace on 2016-06-02T20:30:08Z (GMT). No. of bitstreams: 1 5774.pdf: 5912926 bytes, checksum: c12ae3c92ffb15555578d0bff0da6cea (MD5) Previous issue date: 2013-12-09 / Universidade Federal de Minas Gerais / The objective of this study was to construct and analyze the psychometric properties of an instrument capable of assessing the anticipatory coping skills for abstinence from substances. For the elaboration of items, 18 classes of the anticipatory coping skills as described in literature and obtained from interviews with people in abstinence from substances have been selected. Each one was described and subclasses, that could represent it, were drafted in the form of 92 items. After a semantic analysis and evidences of content validity made by referees, the instrument contains now 68 items. This version was submitted to tests to check application procedures and interpretation of responses, therefore another item was deleted, with others being rewritten. The instrument with 67 items was named Inventory of Anticipatory Coping Skills Inventory for the Abstinence from Alcohol and Other Drugs (IDHEA-AD, as in portuguese). To check evidences of its internal structure validity, it was subjected to Exploratory Factor Analysis (EFA). The samples for this stage were 422 people in treatment for alcohol or crack cocaine abuse or dependence. The data obtained were considered adequate for performing factorial analysis, with KMO index of 0.88 and significant Bartlett sphericity test (&#967; ² = 9032.1, p < 0.001). The Maximum Likelihood method of extraction was used with Promax rotation and variables with factorial loading lower than 0.40 supressed. A structure composed of three factors revealed itself adequate and reliable, with 30 items, Cronbach's alpha of 0.88 and total explained variance of 43.02%. The first factor, named "Assertiveness and planning for high-risk situations of substance use" is composed of 14 items with a Cronbach s alpha of 0.89 and mainly involves refusal skills to the offer of substances. The second, "Expression of positive feelings for abstinence sustenance" is related to ability to demonstrate affection, which contributes to the development of less stressful social situations. It has eight items and Cronbach s alpha of 0.83. Finally, the third factor "Emotional self-control facing adverse situations" involves mainly the self-control of anger, has eight items and Cronbach s alpha of 0.77. This structure also showed good evidence of convergent validity by construct-related (self-efficacy for abstinence), concurrent criterion validity (with level of involvement with the substance and abstinence length), reliability for temporal stability and reliability by consistency in relation to the content. Furthermore, as expected, it was observed that variables such as gender, educational level and type of consumed substance seem not to affect the obtained results. When using the instrument to characterize the repertoire of coping skills in substance dependents or abusers, only abstinence length has proved to be a critical variable. A longer abstinence is related to a higher repertoire of anticipatory coping skills. All results indicate the quality of the IDHEA-AD, which allows the proceeding of the investigation in order to meet the requirements set by the Federal Council of Psychology, so it can be used by professionals in the clinical evaluation. / O objetivo deste estudo foi construir e analisar as propriedades psicométricas de um instrumento capaz de avaliar habilidades de enfrentamento antecipatório para a abstinência de substâncias. Para a redação dos itens, foram selecionadas 18 classes de habilidades de enfrentamento antecipatório descritas na literatura e obtidas de entrevistas com pessoas em abstinência de substâncias. Cada uma foi descrita e subclasses que poderiam representá-la foram redigidas na forma de 92 itens. Após análise semântica e de evidências de validade de conteúdo por juízes, o instrumento passou a conter 68 itens. Esta versão foi submetida a testes para avaliar procedimentos de aplicação e interpretação das respostas e mais um item foi excluído, com outros sendo reescritos. O instrumento com 67 itens recebeu o nome de Inventário de Habilidades de Enfrentamento Antecipatório para a Abstinência de Álcool e Outras Drogas (IDHEA-AD). Para verificar evidências de validade da sua estrutura interna, ele foi submetido à Análise Fatorial Exploratória (AFE). A amostra para esta etapa foi de 422 pessoas em tratamento por abuso ou dependência de álcool ou crack. Os dados obtidos foram considerados adequados para a realização de análise fatorial, com índice KMO de 0.88 e Teste de Esfericidade de Bartlett significativo (&#967;² = 9032.1; p < 0.001). Foi utilizado o método de extração Máxima Verossimilhança, com rotação Promax e supressão de variáveis com carga fatorial inferior a 0,40. Uma estrutura composta por três fatores se mostrou adequada e confiável, com 30 itens, alfa de Cronbach de 0.88 e total de variância explicada de 43.02%. O primeiro fator, nomeado Assertividade e planejamento para situações de alto risco de consumo de substâncias , composto por 14 itens e com alfa de 0.89, envolve principalmente habilidades para recusar oferta de substâncias. O segundo, Expressão de sentimento positivo para manutenção da abstinência está relacionado a habilidades para demonstração de afeto, que colabora para o estabelecimento de situações sociais menos estressoras. Possui oito itens e alfa de 0.83. Por fim, o terceiro fator Autocontrole emocional de situações adversas , envolvendo principalmente autocontrole da raiva, tem oito itens e alfa de 0.77. Esta estrutura apresentou também boas evidências de validade convergente por construto relacionado (autoeficácia para a abstinência), validade de critério concorrente (com nível de envolvimento com a substância e tempo de abstinência), fidedignidade por estabilidade temporal e fidedignidade por consistência em relação ao conteúdo. Além disso, como esperado, observou-se que variáveis como gênero, escolaridade e tipo de substância consumida não parecem interferir nos resultados obtidos. Ao utilizar o instrumento para caracterizar o repertório de habilidades de enfrentamento em abusadores ou dependentes de substâncias, apenas tempo de abstinência mostrou ser uma variável crítica. Maior tempo de abstinência está relacionado a repertório mais elevado de habilidades de enfrentamento antecipatório. Todos os resultados indicam qualidade do IDHEA-AD, o que permite prosseguir com as investigações, de forma a atender aos requisitos exigidos pelo Conselho Federal de Psicologia para que possa ser utilizado por profissionais, na avaliação clínica.

A esclerose múltipla (EM) é considerada doença rara no país, porém tem um grande impacto econômico na sociedade, pois é uma das causas mais importantes de incapacidade em adultos jovens. A doença manifesta-se através de surtos, ou seja, pioras neurológicas agudas, com sintomas instalando-se em horas ou poucos dias. O tratamento do surto é altamente eficaz, podendo reverter o déficit neurológico estabelecido. A única forma regulamentada de tratamento é através da internação em hospital, porém poderia ser realizado em regime de hospital-dia que, contudo, não é previsto pelo Sistema Único de Saúde. Este é um estudo de custo-minimização, desenvolvido com o objetivo de comparar os custos do tratamento do surto de EM à base de corticóide, em regime de internação e regime de hospital-dia, com o objetivo de confirmar a economia deste último. Verificaram-se todos os materiais, medicamentos e profissionais necessários ao tratamento de pulsoterapia com metilprednisolona em pacientes com EM. Esta lista foi orçada tomando-se como referência os valores praticados pelo Hospital de Clínicas de Porto Alegre em sua última compra. Além disto, os valores salariais foram baseados no piso salarial das categorias de profissionais envolvidos no tratamento. Idealizou-se um hospital-dia com 12 leitos, respeitando todas as recomendações do Ministério da Saúde. Os custos do tratamento completo em regime de internação e em hospital-dia foram respectivamente R$ 564,23 e R$ 172,41 - uma redução absoluta de R$ 391,82 e relativa de 69,44%. O levantamento do número de Autorizações de Internação Hospitalar (AIHs) para tratamento de surto de esclerose múltipla em todo o país foi de 10.157 no período de 2002 a 2006. Considerando todo este período, o número de diárias hospitalares (pacientes-dia) que poderiam ter estado disponíveis para ocupação por outras patologias foi de 93.816. Concluiu-se que o tratamento do surto da esclerose múltipla em hospital-dia é bem mais econômico que o regime de internação, promovendo uma potencial relevante economia à sociedade, permitindo melhor utilização dos leitos hospitalares. / Multiple sclerosis is considered a rare disease in Brazil; however has a great economical impact in our society, and is known as one of the most important causes of disability among young adults. Multiple sclerosis is characterized by neurological relapses, occurring in a period of hours or a few days. The treatment of relapses with corticosteroids in high doses is highly effective in relieving the neurological deficit. It can be administered as inpatient or outpatient basis, the last not authorized by the Brazilian Public Health System. This is a cost-minimization analysis in order to compare the costs of this treatment as inpatient to outpatient. We checked the costs of all materials, medications and professionals necessary for this procedure, based in the reference prices practiced at Hospital de Clínicas de Porto Alegre. Moreover, the costs of the professionals involved in this procedure were based on those practiced and suggested by the health labor union in our district. We planned an ideal day-hospital for the outpatient basis treatment, characterized by “twelve simultaneous armchairs”, following all the recommendations from the Brazilian Ministry of Health. The estimated costs of treatment were R$ 564,23 and R$ 172,41, for inpatient and outpatient basis, respectively. This represented a saving of R$ 391,82, meaning a relative reduction of 69,44% in total costs. The number of inpatient basis treatment from 2002 through 2006 in Brazil as a whole, was 10.157. If those patients could have been submitted to an outpatient basis treatment, it would have saved of 93.816 hospital beds. The treatment of relapses of multiple sclerosis as outpatient basis is less expensive than inpatient treatment, promoting an economy for the society, and allowing a better and more rational utilization of hospital beds.

abstract: Relapse after tumor dormancy is one of the leading causes of cancer recurrence that ultimately leads to patient mortality. Upon relapse, cancer manifests as metastases that are linked to almost 90% cancer related deaths. Capture of the dormant and relapsed tumor phenotypes in high-throughput will allow for rapid targeted drug discovery, development and validation. Ablation of dormant cancer will not only completely remove the cancer disease, but also will prevent any future recurrence. A novel hydrogel, Amikagel, was developed by crosslinking of aminoglycoside amikacin with a polyethylene glycol crosslinker. Aminoglycosides contain abundant amount of easily conjugable groups such as amino and hydroxyl moieties that were crosslinked to generate the hydrogel. Cancer cells formed 3D spheroidal structures that underwent near complete dormancy on Amikagel high-throughput drug discovery platform. Due to their dormant status, conventional anticancer drugs such as mitoxantrone and docetaxel that target the actively dividing tumor phenotype were found to be ineffective. Hypothesis driven rational drug discovery approaches were used to identify novel pathways that could sensitize dormant cancer cells to death. Strategies were used to further accelerate the dormant cancer cell death to save time required for the therapeutic outcome. Amikagel’s properties were chemo-mechanically tunable and directly impacted the outcome of tumor dormancy or relapse. Exposure of dormant spheroids to weakly stiff and adhesive formulation of Amikagel resulted in significant relapse, mimicking the response to changes in extracellular matrix around dormant tumors. Relapsed cells showed significant differences in their metastatic potential compared to the cells that remained dormant after the induction of relapse. Further, the dissertation discusses the use of Amikagels as novel pDNA binding resins in microbead and monolithic formats for potential use in chromatographic purifications. High abundance of amino groups allowed their utilization as novel anion-exchange pDNA binding resins. This dissertation discusses Amikagel formulations for pDNA binding, metastatic cancer cell separation and novel drug discovery against tumor dormancy and relapse. / Dissertation/Thesis / Doctoral Dissertation Bioengineering 2016

The Swedish prison and probation service is an authority whose task is to care for individuals sentenced to imprisonment or probation (Kriminalvården, 2018). I also chose to include social services, SIS and outpatient care for a broader ground for my study. The purpose of the study is to investigate how the Swedish prison and probation service and agency in Norrbotten County work with relapse prevention in young criminal men. I chose to use a qualitative method to gain a broad understanding of this subject. The result has been collected through six semi-structured interviews and semi structured telephone interviews with persons working in the Swedish prison and probation service, SiS, outpatient care and social services in Norrbotten County. The results show that these activities work against the relapse risk through motivational conversations, treatment plans, and the creation of relationships between them and the client. All of these factors is used to counteract the labelling that the young men received from society when they deviated from the norms and laws of society. This can make the young men to easily return in relapse after the execution. Other factors such as anti-social networks, homelessness, lack of economy and unemployment are also negative contributing causes that affect the return risk. / Kriminalvården är en myndighet vars uppgift är att vårda individer som dömts till fängelse eller frivård (Kriminalvården, 2018). Till Kriminalvården räknas även frivården med. Jag valde även att inkludera Socialtjänsten, SiS och Öppenvården för att få en bredare underlag för min studie. Syftet för studien är att undersöka hur Kriminalvården och samverkande verksamheter i Norrbottens län arbetar med återfallsprevention hos unga kriminella män. Jag valde att använda mig av en kvalitativ metod för att få en bred förståelse kring detta ämne.  Resultatet har samlats in via sex semistukturerade intervjuer samt semistukturerade telefonintervjuer med personer som jobbar inom Kriminalvården, Frivården, SiS, Öppenvården och Socialtjänsten inom Norrbottens län. Resultatet visar att dessa verksamheter jobbar mot återfallsrisken genom motiverande samtal, behandlingsplaner och skapande av relationer mellan dem och klienten.  Alla dessa faktorer används för att motverka den stämpling som de unga männen fått av samhället när de avvikit från normerna och lagarna i samhället. Detta gör att de unga männen lätt kan hamna tillbaka i återfall efter avslutad tid. Andra faktorer såsom antisociala nätverk, bostadslöshet, brist på ekonomi och arbetslöshet är också negativt bidragande orsaker som påverkar återfallsrisken.

Submitted by Daniele Amaral (daniee_ni@hotmail.com) on 2017-10-09T19:23:49Z No. of bitstreams: 1 DissPP.pdf: 2336243 bytes, checksum: 6713ce2a544f0c9590312b61ae159504 (MD5) / Approved for entry into archive by Ronildo Prado (producaointelectual.bco@ufscar.br) on 2017-10-31T13:11:51Z (GMT) No. of bitstreams: 1 DissPP.pdf: 2336243 bytes, checksum: 6713ce2a544f0c9590312b61ae159504 (MD5) / Approved for entry into archive by Ronildo Prado (producaointelectual.bco@ufscar.br) on 2017-10-31T13:11:59Z (GMT) No. of bitstreams: 1 DissPP.pdf: 2336243 bytes, checksum: 6713ce2a544f0c9590312b61ae159504 (MD5) / Made available in DSpace on 2017-10-31T13:16:14Z (GMT). No. of bitstreams: 1 DissPP.pdf: 2336243 bytes, checksum: 6713ce2a544f0c9590312b61ae159504 (MD5) Previous issue date: 2017-05-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Context-induced reinstatement of drug seeking is an animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in prelimbic cortex has been implicated in context-induced reinstatement drug seeking. Here, we report a new and feasible training procedure for context-induced reinstatement of alcohol seeking to explore the role of prelimbic cortex in context-induced relapse to alcohol seeking. Long-Evans rats were first given home-cage access to 10% ethanol. Using a saccharin fading technique, rats were first trained to self-administer 10% ethanol in one context. Next, lever pressing in the presence of the discrete cue was extinguished in a different context. Subsequently, context-induced reinstatement of drug seeking was assessed by re-exposing rats to the drug-associated or extinction context under extinction conditions. Re-exposure to the alcohol-associated context reinstated alcohol seeking and increased expression of the neural activity marker Fos in the prelimbic prefrontal cortex. The percentage of neural activation in this brain region was 3.4 % in extinction context and 7.7 % in drug associated context. Reversible inactivation of neural activity in prelimbic prefrontal cortex using GABA agonists muscimol and baclofen attenuated context-induced reinstatement. Based on previous findings of the literature that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in prelimbic cortex and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the GABAα5 gene and decrease in the AMPA receptor subunit genes GluR1 and GluR2 in only Fos-positive neurons. Our results demonstrate an important role of prelimbic cortex in context-induced reinstatement of alcohol seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons. / Uma das principais dificuldades relacionada ao tratamento da dependência de etanol é o alto índice de reincidência ao uso dessa substância. Neste sentido, a exposição ao contexto associado ao uso de etanol é a principal causa de recaída. Evidencias mostram que a recaída envolve comportamentos de aprendizado associativo. Essas associações são armazenadas por pequenos grupamentos neurais conhecidos como “neuronal ensembles”. A recaída induzida pelo contexto pode ser estudada através de um modelo animal conhecido como “ABA renewal”. Neste procedimento, ratos são treinados a autoadministrarem etanol em um determinado contexto. Após o aprendizado, os roedores são submetidos ao procedimento de extinção desse comportamento, em um ambiente com diferenças táteis, visuais e sonoras do contexto do treino. A reinstalação é avaliada através da exposição do animal ao contexto inicial. O objetivo do presente estudo foi: a) comparar o desempenho de ratos Wistar e Long-Evans no protocolo de reinstalação da autoadministração de etanol induzida pelo ambiente; b) investigar a participação do córtex pré-frontal medial nesse comportamento; c) investigar a presença de alterações na expressão gênica em “neuronal ensembles” do córtex pré-límbico, relacionadas a reinstalação da autoadministração de etanol. Observamos quea exposição ao contexto previamente associado a autoadministração de etanol foi capaz de reinstalar esse comportamento em ratos Long-Evans e Wistar. Sendo que a linhagem de ratos Long-Evans apresentou melhor desempenho no teste de reinstalação da autoadministração de etanol induzida pelo contexto quando comparado aos ratos Wistar. Demonstramos que a reinstalação da autoadministração de etanol induzida pelo contexto promoveu aumento da ativação neuronal do córtex pré-límbico. Notamos ainda, que uma pequena porcentagem de neurônios foi ativada no córtex pré-límbico durante a reinstalação da autoadministração de etanol induzida pelo contexto (~7,7%). Evidenciamos que a inibição farmacológica do córtex pré-límbico atenuou a reinstalação da autoadministração de etanol induzida pelo contexto. E por fim, encontramos que a reinstalação da autoadministração de etanol foi associada a redução na expressão de GluR1 e GluR2 (subunidades do receptor glutamatérgico AMPA) e ao aumento na expressão de GABAα5 (subunidade do receptor GABAérgico GABA A) em neurônios seletivamente ativados no córtex pré-límbico durante o teste comportamental. Concluímos que a reinstalação da autoadministração de etanol induzida pelo ambiente é mediada por alterações na expressão gênica em “neuronal ensembles” ativados pela associação entre o efeito reforçador do etanol e o contexto em que essa substância de abuso foi administrada.

Submitted by TATIANE FERNANDA SYLVESTRE null (thaty_sylvestre@hotmail.com) on 2018-03-09T14:15:45Z No. of bitstreams: 1 Doutorado versão final correções.pdf: 1948063 bytes, checksum: 67732e30851ac4f403a6e63c147faa2f (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2018-03-09T17:35:41Z (GMT) No. of bitstreams: 1 sylvestre_tf_dr_bot.pdf: 3415633 bytes, checksum: af28727bb056bb44e01fe82328f62eec (MD5) / Made available in DSpace on 2018-03-09T17:35:42Z (GMT). No. of bitstreams: 1 sylvestre_tf_dr_bot.pdf: 3415633 bytes, checksum: af28727bb056bb44e01fe82328f62eec (MD5) Previous issue date: 2018-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A paracoccidioidomicose (PCM) é uma doença sistêmica causada por fungos termodimórficos do complexo Paracoccidioides brasiliensis - P. brasiliensis e P. lutzii. Pacientes com PCM revelam comprometimento imune celular específico. Apesar do tratamento efetivo, os fungos quiescentes podem levar à recaída, geralmente tardia, cujo diagnóstico sorológico tem se mostrado pouco sensível. A sensibilidade do teste de imunodifusão é de cerca de 90% em pacientes com PCM não tratados, mas de apenas 45% em casos de recaída. Além disso, o soro de pacientes com PCM causada por P. lutzii, freqüente na região Centro-Oeste do Brasil, não reage com o antígeno clássico obtido do Pb B-339. No seguimento dos pacientes, continua a busca de um critério que dê maior segurança à decisão de se suspender o tratamento. Esses achados mostraram a necessidade de métodos alternativos de diagnóstico e seguimento, como os utilizados em proteômica, que constituiram o presente estudo. Assim, proteínas expressas no soro de pacientes com PCM em atividade - não tratada (causada por P. brasiliensis e por P. lutzii), com recaída da doença (causada por P. brasiliensis) e de controles saudáveis foram identificadas usando-se abordagem proteômica, realizada em quatro etapas - quantificação de proteínas, digestão de proteínas em solução, sequenciamento de peptídeos por espectrometria de massa e análise de dados para identificação de proteínas. Foram identificadas 29 proteínas plasmáticas à admissão, cuja comparação entre os grupos de pacientes sugeriu que a presença da immunoglobulin (Ig) alpha-2 chain C region e a ausência de Ig heavy chain V-III TIL indicariam infecção por P. lutzii e que a ausência da proteína complement factor B poderia ser um preditor de recaída. Na análise evolutiva das proteínas identificadas em pacientes com PCM por P. brasiliensis em tratamento, comparando-se aqueles que apresentaram com os que não revelaram recaída, 29 proteínas foram identificadas. As interações observadas entre as proteínas, usando transferrin e haptoglobin como a principal proteína de ligação, foram fortes com todas as demais. O acompanhamento desses pacientes sugere que a presença de cerulosplamin pode ser um marcador de recaída e que a de transferrin e a apolipoprotein A-II podem contribuir para a avaliação da cura e suspensão do tratamento, evitando que esta decisão seja muito precoce. A avaliação das proteínas selecionadas, identificadas por metodologia proteômica, deve ser realizada em um número maior de pacientes, para validar esses achados. / Paracoccidioidomycosis (PCM) is a systemic disease caused by thermodymorphic fungi of the Paracoccidioides brasiliensis complex - P. brasiliensis and P. lutzii. Patients with PCM reveal specific cellular immune impairment. Despite the effective treatment, quiescent fungi can lead to relapse, usually late, whose serological diagnosis has presented low sensitivity. The double agar gel immunodiffusion test shows a 90% sensitivity in untreated PCM patients, but it is much lower (45%) in cases of relapse. In addition, serum from patients with PCM caused by P. lutzii, frequent in the Midwest region of Brazil, do not react with the classical antigen obtained from Pb B-339. In the follow-up of the patients, persists the search of a criterium that gives a higher safety for treatment discontinuation. These findings showed the need for alternative methods for diagnosis and follow-up, such as those based on proteomics, which constituted the present study. Thus, serum expressed proteins from patients with active - untreated PCM (caused by P. brasiliensis and by P. lutzii), from relapsed PCM patients (caused by P. brasiliensis) and from healthy controls were identified using a proteomic approach, performed in four steps - protein quantification, protein digestion in solution, peptide sequencing by mass spectrometry and data analysis for protein identification. A total of 29 plasma proteins were identified at admission (before introduction of the treatment), and the comparison regarding groups suggested that the presence of the immunoglobulin (Ig) alpha-2 chain C region and the absence of heavy chain Ig V-III TIL are indicative of infection by P. lutzii and that the absence of the complement factor B protein may be a predictor of relapse. The evaluation of the proteins during the treatment follow-up of the PCM patients infected by P. brasiliensis, separated regarding the presence of relapse, identified 29 proteins. The interactions observed between the proteins, using transferrin and haptoglobin as the main binding protein, were strong with all the others. Patients’ follow-up suggests that cerulosplamin may be a marker of relapse and that transferrin and apolipoprotein A-II may contribute to the evaluation of cure and discontinuation of treatment, avoiding that this decision is too early. The study of the selected proteins in a higher number of patients should be carried out in order to validate these findings.

A esclerose múltipla (EM) é considerada doença rara no país, porém tem um grande impacto econômico na sociedade, pois é uma das causas mais importantes de incapacidade em adultos jovens. A doença manifesta-se através de surtos, ou seja, pioras neurológicas agudas, com sintomas instalando-se em horas ou poucos dias. O tratamento do surto é altamente eficaz, podendo reverter o déficit neurológico estabelecido. A única forma regulamentada de tratamento é através da internação em hospital, porém poderia ser realizado em regime de hospital-dia que, contudo, não é previsto pelo Sistema Único de Saúde. Este é um estudo de custo-minimização, desenvolvido com o objetivo de comparar os custos do tratamento do surto de EM à base de corticóide, em regime de internação e regime de hospital-dia, com o objetivo de confirmar a economia deste último. Verificaram-se todos os materiais, medicamentos e profissionais necessários ao tratamento de pulsoterapia com metilprednisolona em pacientes com EM. Esta lista foi orçada tomando-se como referência os valores praticados pelo Hospital de Clínicas de Porto Alegre em sua última compra. Além disto, os valores salariais foram baseados no piso salarial das categorias de profissionais envolvidos no tratamento. Idealizou-se um hospital-dia com 12 leitos, respeitando todas as recomendações do Ministério da Saúde. Os custos do tratamento completo em regime de internação e em hospital-dia foram respectivamente R$ 564,23 e R$ 172,41 - uma redução absoluta de R$ 391,82 e relativa de 69,44%. O levantamento do número de Autorizações de Internação Hospitalar (AIHs) para tratamento de surto de esclerose múltipla em todo o país foi de 10.157 no período de 2002 a 2006. Considerando todo este período, o número de diárias hospitalares (pacientes-dia) que poderiam ter estado disponíveis para ocupação por outras patologias foi de 93.816. Concluiu-se que o tratamento do surto da esclerose múltipla em hospital-dia é bem mais econômico que o regime de internação, promovendo uma potencial relevante economia à sociedade, permitindo melhor utilização dos leitos hospitalares. / Multiple sclerosis is considered a rare disease in Brazil; however has a great economical impact in our society, and is known as one of the most important causes of disability among young adults. Multiple sclerosis is characterized by neurological relapses, occurring in a period of hours or a few days. The treatment of relapses with corticosteroids in high doses is highly effective in relieving the neurological deficit. It can be administered as inpatient or outpatient basis, the last not authorized by the Brazilian Public Health System. This is a cost-minimization analysis in order to compare the costs of this treatment as inpatient to outpatient. We checked the costs of all materials, medications and professionals necessary for this procedure, based in the reference prices practiced at Hospital de Clínicas de Porto Alegre. Moreover, the costs of the professionals involved in this procedure were based on those practiced and suggested by the health labor union in our district. We planned an ideal day-hospital for the outpatient basis treatment, characterized by “twelve simultaneous armchairs”, following all the recommendations from the Brazilian Ministry of Health. The estimated costs of treatment were R$ 564,23 and R$ 172,41, for inpatient and outpatient basis, respectively. This represented a saving of R$ 391,82, meaning a relative reduction of 69,44% in total costs. The number of inpatient basis treatment from 2002 through 2006 in Brazil as a whole, was 10.157. If those patients could have been submitted to an outpatient basis treatment, it would have saved of 93.816 hospital beds. The treatment of relapses of multiple sclerosis as outpatient basis is less expensive than inpatient treatment, promoting an economy for the society, and allowing a better and more rational utilization of hospital beds.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Amphetamine compounds and its derivatives are widely used in clinical medicine, but it is known that frames can cause dependence, tolerance and withdrawal. Furthermore, these drugs can alter metabolism and the functions of central neurotransmitters causing oxidative imbalances. In this sense it is already documented that exercise improves the conditions of well-being and self-esteem, and improve the plasticity and thus neuronal protection. In this context, the present study aimed to evaluate the influence of regular and continuous exercise on anxiety and behavioral parameters related to relapse to the use of amphetamine in an animal model of conditioned place preference (CPP). Male Wistar rats were conditioned to the use of AMPH or vehicle for 14 days and then half of each group was subjected to aerobic, regular and continuous physical activity for 5 weeks, while the others were not exercised. At the end of the last exercise session, the animals were re-conditioned to the use of AMPH/vehicle for more 3 days. After this phase, the animals were subjected to behavioral testing CPP to evaluate relapse to drug use, and the elevated plus maze to measure anxiety parameters. Hippocampal oxidative status was evaluated by levels of generation of reactive species (RS), carbonyl protein (CP), and activity levels of catalase (CAT) and Na+K+-ATPase, respectively. It was observed that the per amphetamine was able to develop is the CPP in the animals, however after the completion of 5 weeks of aerobic exercise, there was a reduction in the rate preferably compared to sedentary rats indicating a lower rate of relapse to amphetamine. In addition, exercise was shown to be beneficial to reduce the degree of anxiety and oxidative damage in these animals by amphetamine. Thus, regular and continuous exercise is a promising tool in the treatment of dependence and relapse to the indiscriminate use of drugs. / Compostos anfetamínicos e seus derivados são amplamente utilizados na clínica médica, porém podem provocar quadros de dependência, tolerância e abstinência. Além disso, estas drogas são capazes de afetar as funções e o metabolismo de neurotransmissores do sistema nervoso central (SNC) provocando desequilíbrios oxidativos. Neste sentido, já é documentado que o exercício físico melhora as condições de bem estar e auto-estima, favorecendo a plasticidade e, consequentemente, a proteção neuronal. Nesse contexto, o presente estudo visou avaliar a influência do exercício físico regular e contínuo sobre parâmetros comportamentais e de ansiedade relacionados à recaída ao uso de anfetamina em modelo animal de preferência condicionada de lugar (PCL). Ratos Wistar adultos foram condicionados com anfetamina no protocolo de PCL ou veículo por 14 dias e, na sequência, metade de cada grupo foi submetida à atividade física aeróbica regular e contínua por 5 semanas, enquanto os demais não foram exercitados. Ao término da última sessão de exercício físico, os animais foram re-condicionados ao uso de anfetamina ou veículo por mais 3 dias. Após esta fase, os animais foram submetidos aos testes comportamentais de PCL para avaliar sintomas de recaída pela preferência à droga, sendo também avaliados parâmetros de ansiedade em labirinto em cruz elevado. O status oxidativo na região do hipocampo foi avaliado através da geração de espécies reativas (RS), dos níveis de proteína carbonilada (PC) e atividade das enzimas catalase (CAT) e Na+K+-ATPase. Observou-se que a anfetamina per se foi capaz de desenvolver a PCL nos animais. Entretanto, após 5 semanas de exercício físico aeróbico regular e contínuo, os animais expostos à anfetamina mostraram menor PCL pela droga quando comparados ao grupo sedentário, indicando menor índice de recaída à anfetamina. Além disso, o exercício físico regular e contínuo exerceu influência favorável ao reduzir o nível de ansiedade e os danos oxidativos cerebrais, os quais foram associados ao condicionamento com anfetamina. Desse modo, o exercício físico regular e contínuo é uma ferramenta promissora no tratamento de dependência e recaída ao uso abusivo de drogas.

Le cancer colorectal est la première pathologie cancéreuse de la sphère digestive, tant en terme de fréquence que de mortalité par an. Chaque année, 41 000 nouveaux cas sont diagnostiqués et 17 000 décès sont dus à ce cancer en France. Deux paramètres cliniques expliquent la mortalité de ce cancer; d'une part le fait qu'un patient sur deux est diagnostiqué au stade métastatique ou va présenter des lésions métastatiques durant l'histoire de sa pathologie, d'autre part le fait que les patients après traitement vont fréquemment présenter une récidive de leur pathologie. L'utilisation de régimes de chimiothérapies avant et après résection métastatique améliore la survie sans récidive à court terme, mais à 2 ans post chirurgie l'avantage apporté est perdu. Ainsi, la compréhension des mécanismes d'échappement à la chimiothérapie et régissant la croissance tumorale est d'intérêt pour tenter de limiter la récidive tumorale. L'objectif de ce travail de thèse a consisté en l'analyse de sous-populations obtenues sous pression de chimiothérapie au 5-Fluorouracile (5FU) dérivées de la lignée cancéreuse colique HT29, ainsi que les mécanismes moléculaires associés. Notre clone le plus chimiorésistant isolé, le modèle cellulaire 5F31, quitte le compartiment prolifératif sous traitement à fortes doses de 5FU, ceci étant associé à une perturbation de la voie de signalisation de la Src kinase c-Yes et de son partenaire, le co-activateur transcriptionnel YAP. Sous traitement, les cellules chimiorésistantes entrent en quiescence, le complexe protéique entre c-Yes et YAP est perdu et la quantité totale et nucléaire de YAP diminue de manière significative (Igoudjil, Touil, Corvaisier et al. 2014 Clinical Cancer Research). Dès lors, la suite des travaux a consisté en l'étude du rôle potentiel de YAP sur la balance quiescence/prolifération sous 5FU. L'inhibition pharmacologique ou l'inhibition transitoire de l'expression de YAP et de son paralogue, la protéine TAZ, dans plusieurs lignées cancéreuses coliques induit l'augmentation de la fraction de cellules quiescentes, associée au ralentissement significatif de la croissance tumorale. A l'inverse, la surexpression d'une forme constitutivement active de YAP demeurant nucléaire sous 5FU maintient les cellules 5F31 en prolifération et sensibilise les cellules à la chimiothérapie. Au niveau des effecteurs protéiques, l'induction de quiescence (par traitement à la chimiothérapie ou inhibition de YAP/TAZ) est associée à la perte d'expression de la Cycline E1 et du facteur de transcription c-Myc. A l'inverse, la surexpression du dominant constitutivement actif de YAP dans les cellules 5F31 conduit à l'expression soutenue de la Cycline E1 sous 5FU, expression nécessitant l'activation du facteur de transcription CREB. L'inhibition de la Cycline E1 permet d'induire la quiescence cellulaire, proposant cette protéine comme l'un des effecteurs des protéines YAP/TAZ dans la régulation entre la quiescence et la prolifération cellulaire (Corvaisier et al, Oncotarget, 2016). En conclusion, nos données montrent l'importance du rôle des protéines YAP/TAZ dans le maintien des cellules en prolifération via l'expression notamment de la Cycline E1. Nos résultats sur cohorte de patients atteints de métastases hépatiques de cancers colorectaux montrent que l'expression des co-activateurs YAP/TAZ est liée à un index prolifératif plus important, confortant nos données sur le rôle de ces protéines dans la croissance tumorale. De plus, l'expression élevée de YAP et TAZ est associée en analyses multivariées à une récidive plus précoce et à une survie globale plus faible. Ainsi, l'étude de l'expression et du niveau d'activation de ces acteurs serait un marqueur pronostic intéressant dans l'anticipation de la récidive métastatique ; ainsi que des cibles thérapeutiques intéressantes pour tenter de limiter la rechute tumorale. / Colorectal cancer is the most frequent and lethal cancerous pathology from the digestive system. Each year in France, 41 000 new cases are diagnosed and 17 000 patients die due to this pathology. This high mortality is mainly due to the rate of patients with liver metastatic lesions and the early relapse of those metastases after treatment. The use of chemotherapy prior to surgery induces a decrease of early relapse, however 2 years after resection this advantage is lost. Thus, understanding the mechanisms underlying escape to treatment is required to try to delay or prevent tumor recurrence.The aim of this doctoral work was to analyze clonal chemoresistant subpopulations derived from the colorectal cancer cell line HT29 after chronic exposure to 5-Fluorouracil (5FU) and molecular mechanisms associated with chemoresistance. The most chemoresistant clonal subpopulation, 5F31, stops its proliferation after treatment with high dose of 5FU, this behavior being associated with the modulation of the c-Yes/YAP axis. After treatment, 5F31 cells enter quiescence, interaction between c-Yes and YAP is lost and total and nuclear YAP protein expression reduces significantly (Igoudjil, Touil, Corvaisier et al. 2014, Clinical Cancer Research). The next step was to study functions of YAP protein in this chemotherapy- induced quiescence.Pharmacological or transient inhibition of YAP and its homolog TAZ, induces quiescence and reduces cellular growth in several colorectal cancer cell lines. On the other hand, overexpression of a constitutively active form of YAP in 5F31 cells forces cells to remain proliferative under 5FU treatment, enhancing 5F31 cell chemosensitivity to 5FU.Regarding proteic effectors, quiescence (either induced by 5FU or YAP/TAZ inhibition) is associated with loss of expression of the transcription factor c-Myc and Cyclin E1. In 5F31 cells expressing the active mutant form of YAP, Cyclin E1 expression is sustained after 5FU treatment through the activation of the transcription factor CREB. Cyclin E1 inhibition is sufficient to induce quiescence, therefore introducing this protein as one of the final effectors of YAP/TAZ co-activators in the regulation of the proliferation/quiescence switch in colorectal cancer cells (Corvaisier et al. 2016, Oncotarget).To conclude, our work reveals the importance of YAP/TAZ proteins for the maintenance of colorectal cancer cells proliferation through Cyclin E1 expression. Our work on liver metastases from patients with colorectal cancer shows that high expression of YAP/TAZ is connected to a higher proliferative index in metastatic lesions. Moreover, high YAP/TAZ expression is associated with shorter patient progression-free survival and shorter overall survival. Studying the expression and level of YAP/TAZ activation could be an interesting prognosis marker to anticipate metastatic relapse and potent druggable target to delay tumoral recurrence.

The aim of this research was to explore the causes of relapse post treatment for substance dependency within the South African Police Services (SAPS). “Alcoholism is a chronic relapsing brain disease, so individuals with substance abuse disorders face the possibility of relapse once they stop using alcohol even if they have had a successful treatment” (Perkinson, 2004:180). According to Connors, Maisto and Donovan (1996:5) research revealed that relapse rates among persons treated for alcoholism were approximately 35% and 58% at two weeks and three months after treatment, respectively. A relapse or uncontrolled return to alcohol or other drug use following competent treatment, is one of the greatest problems substance abusers and their counselors face (Lewis, Dana&Blevins, 2002:105; Johnson, 2003:271). The objective of the study was to explore the challenges that members in the South African Police Services (SAPS) experience or are exposed to causing them to relapse post treatment for substance dependency. The findings are intended to provide recommendations to the management of SAPS to develop a relapse prevention programme in the workplace to prevent relapse post treatment. The researcher utilized a quantitative research approach to identify the causes of relapse among SAPS members post rehabilitation for substance dependency. The type of research is applied research as the focus of the study is on identifying the causes for members within the SAPS to relapse post treatment for substance dependency and to address a specific practical issue in the workplace. The literature review focused on understanding the relapse process. The cognitive-behavioural Model of relapse was discussed at length including the prevalence of substance abuse among police members and concluded with information on the relapse prevention programme. A self-administered questionnaire was used as a research tool to collect data from the respondents (See annexure C). The population of this study was the members of the SAPS who had undergone treatment for substance dependency from January 2008 to April 2009. The researcher concentrated on those members in the KZN Province. Consultation with the social workers revealed a population size of 50 members. Due to the small size of the population, no sampling procedure was necessary as the whole population was selected as the sample. The findings of the study were based on 44 questionnaires that were returned by the respondents. The findings were analyzed and presented using tables and graphs which were then interpreted in words. The study revealed that the majority of the respondents attributed their main cause for relapse due to Intrapersonal determinants - they experienced a negative emotional state (for example, feelings of anger, frustration and anxiety) that initially triggered their need to taking that first drink. Secondly respondents identified exposure to peer pressure and boredom as also being a cause for their relapse. They disclosed that at times their peers would pressurize them to consume alcohol. The temptation, urges and cravings and being in the presence of other people consuming alcohol proved too difficult to resist. Alcohol being the recreational drug of choice proved to be tempting to members especially when socialising with colleagues. Based on the findings of the study conclusions and recommendations were made to the development of the relapse prevention programme to assist members post treatment to maintain their sobriety. Copyright / Dissertation (MA)--University of Pretoria, 2012. / Social Work and Criminology / unrestricted